Fumaric acid does not have a single defined target but acts through multiple mechanisms. It exerts anti-inflammatory effects by inhibiting the p38 MAPK-dependent NF-κB signaling pathway. It has an immunosuppressive and immunomodulating effect by inhibiting T and B lymphocytes. It is also a Th1 cell inhibitor. In the context of multiple sclerosis, it has a relapse-reducing effect by releasing the cell protection factor Nrf2.

In vitro, fumaric acid exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway dependent on p38 MAPK. It attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling. It provides intracellular energy in the form of ATP as an intermediate of the citric acid cycle.

In vivo, fumaric acid has been used in the study of pregnancy-induced hypertension. In multiple sclerosis, the acid has a relapse-reducing effect by releasing the cell protection factor Nrf2. It exerts anti-inflammatory effects through modulation of immune responses and inhibition of NF-κB signaling.

Cell-free assays for fumaric acid are not typical because it is an endogenous metabolite. Its inhibition of NF-κB signaling can be assessed using reporter assays or electrophoretic mobility shift assays (EMSA) with nuclear extracts. Its ability to modulate p38 MAPK activity can be assessed using kinase activity assays. Its purity is confirmed by HPLC.

Cellular assays for fumaric acid are performed using various cell types, including fibroblasts and immune cells. Cells are treated with varying concentrations of fumaric acid, and NF-κB activation is assessed by measuring p65 nuclear translocation or IκBα degradation. p38 MAPK phosphorylation is assessed by Western blotting. Cytokine production is measured by ELISA.

In vivo animal experiments for fumaric acid are conducted in models of multiple sclerosis, pregnancy-induced hypertension, and other inflammatory conditions. Animals are administered fumaric acid orally or via other routes, and disease severity, inflammatory markers, and histopathology are assessed. Its immunomodulatory effects are evaluated.

Absorption, Distribution and Excretion
In four healthy subjects, the total activity of labeled carbon dioxide in the blood entering and leaving the brain was measured after a single injection of fumarate-2-(14)C. Blood samples were simultaneously drawn from the femoral artery and the superior bulb of the internal jugular vein. Cerebrospinal fluid samples were also collected. The results showed that (14)CO2 was immediately generated in the brain after the injection of the isotope. This indicates that fumarate can easily cross the blood-brain barrier. Metabolism/Metabolites Fumarate is an intermediate product of the citric acid cycle, which cells use to generate energy from food, existing in the form of adenosine triphosphate (ATP). It is produced by the oxidation of succinate by succinate dehydrogenase. Fumarate is then converted to malate by fumarate hydratase (fumarate hydratase).
Fumaric acid has a molecular weight of 116.07 g/mol and a molecular formula of C4H4O4. It is a white crystalline powder with a melting point of 287°C. It is soluble in water and organic solvents. It should be stored under recommended conditions. Its pKa values are 3.03 and 4.44.

Fumaric acid is generally considered safe. It is a naturally occurring compound and an intermediate in the citric acid cycle. No significant toxicity has been reported at physiological concentrations. At high doses, it may cause gastrointestinal irritation. Its safety is well established through its use as a food additive and in pharmaceutical formulations.

[1]. Fumaric aciduria: a new organic aciduria, associated with mental retardation and speech impairment. Clin Chim Acta. 1983 Aug 31;132(3):301-8.

[2]. Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling. Food Chem Toxicol. 2013 Aug;58:423-31.

[3]. Fumaric acid and succinic acid treat gestational hypertension by downregulating the expression of KCNMB1 and TET1. Exp Ther Med. 2021 Oct;22(4):1072.

Fumaric acid is a colorless crystalline solid. Its main hazard lies in its environmental threat. Immediate measures should be taken to limit its spread into the environment. Fumaric acid is flammable but may be difficult to ignite. It is used in the manufacture of paints and plastics, food processing and preservation, and other applications. Fumaric acid is a butenedioic acid with an E-type configuration of its C=C double bond. It is an intermediate metabolite in the citric acid cycle. It functions as a food acidity regulator, a basic metabolite, and an anti-aging agent. It is the conjugate acid of fumaric acid (1-). Fumaric acid is present in or produced by Escherichia coli (K12 strain, MG1655 strain). Fumaric acid has been reported in Phomopsis velata, Tropicoporus linteus, and other organisms with relevant data. Fumaric acid is a precursor of L-malic acid in the Krebs tricarboxylic acid cycle. It is produced by the oxidation of succinate by succinate dehydrogenase. Fumaric acid is converted to malic acid by fumarate enzymes. Fumarates are salts or esters of the organic compound fumaric acid (a dicarboxylic acid). Fumaric acid has recently been identified as a carcinogenic metabolite (A15199). As a food additive, fumaric acid is used to impart a sour taste to processed foods. Fumaric acid is also used as an antifungal agent in packaged foods such as cake mix, flour, and tortillas. Furthermore, fumaric acid is added to bread to increase the porosity of baked goods. It is also used to impart a sour taste to sourdough and rye bread. In cake mix, fumaric acid helps maintain a low pH, preventing the flour from clumping. In fruit juices, fumaric acid helps maintain a low pH, thus helping to stabilize flavor and color. When used in combination with sodium benzoate, fumaric acid can also inhibit the growth of E. coli in beverages. When added to wine, fumaric acid helps prevent further fermentation while maintaining a low pH and removing trace metals, thus stabilizing the wine's flavor. Fumaric acid can also be added to dairy products, sports drinks, jams, jellies, and candies. Fumaric acid helps break down the bonds between gluten proteins in wheat, making dough more elastic. Fumaric acid is also used in paper sizing, printer toner, and polyester resins used to manufacture molded walls.
Fumaric acid is an endogenous metabolite and an intermediate of the citric acid cycle. It exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway dependent on p38 MAPK. It has immunosuppressive and immunomodulating effects. It is used in the treatment of psoriasis and multiple sclerosis as part of fumaric acid esters. It is also a food additive.

C4H4O4

116.07

116.01

110-17-8

9003-16-1

444972

White to off-white solid powder

1.5±0.1 g/cm3

355.5±25.0 °C at 760 mmHg

298-300 °C (subl.)(lit.)

183.0±19.7 °C

0.0±1.7 mmHg at 25°C

1.526

-0.01

2

4

2

8

119

0

C(=C/C(=O)O)\C(=O)O

VZCYOOQTPOCHFL-OWOJBTEDSA-N

InChI=1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+

(E)-but-2-enedioic acid

Lichenic acid; Kyselina fumarova; Fumaric acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~25 mg/mL (~215.39 mM)
H2O : ~11.11 mg/mL (~95.72 mM)

Solubility in Formulation 1: 8.33 mg/mL (71.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)